This is a new application from the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) Clinical Trials network. By the end of 2014, the network will have completed 4 clinical trials testing 7 interventions in approximately 1000 women ages 40-62 with vasomotor (VMS) and other menopause symptoms. In the new application, we propose to conduct a large multicenter trial on a relatively understudied area of menopause - vaginal health and sexual function. The number of US women over age 65 is expected to double by 2022 and approximately 40% will experience bothersome vaginal symptoms, 75% may have vaginal dryness and up to 40% may experience pain with intercourse. To address this vast, understudied problem, we propose in Specific Aim #1 to conduct a 3-arm, randomized, controlled, double-blind, clinical trial among postmenopausal women ages 45-70. We will evaluate the effectiveness of ultra-low dose vaginal estradiol (Vagifem 10 mcg), non-hormonal hydrophilic non-prescriptive vaginal gel (Replens) and placebo in reducing a composite score of vaginal symptoms (dryness, itching, irritation or soreness). Secondary aims include evaluation of sexual function, quality of life, and genitourinary atrophy and the creation of a biorepository of vaginal and blood specimens. In a subset of women, we will also examine whether treatment response is related to: a) the postmenopausal vaginal microbiome; b) vaginal mucosal inflammation; and c) reproductive hormone profiles. The in-depth focus on the mechanisms associated with postmenopausal vaginal symptoms will use state of the art microbiologic techniques on longitudinally collected biologic specimens and will guide future translational studies. Specific Aim #2 addresses common problems for many midlife women and their providers: a) menopausal symptom management decisions can be challenging, due to rapidly changing and sometimes contradictory data on treatment safety and efficacy; and b) individualized decision aids to help women feel fully informed about various menopausal treatment options are lacking. To translate and disseminate our findings on postmenopausal vaginal health, in addition to findings from prior trials on vasomotor, sleep, mood and pain symptoms, we propose to develop and pilot test a comprehensive, state-of- the-art, tailored, multi-media materials aimed at facilitating informed menopausal decision-making for symptomatic women and their providers. Involvement of midlife women and healthcare providers at every stage in the process has been incorporated. This application is novel and transformative for: 1) proposing the first adequately powered, double-blind, placebo-controlled trial of hormonal and non-hormonal treatments for postmenopausal vaginal symptoms; and 2) for providing the first, multi-media menopause decision aid that encompasses the latest evidence surrounding all available therapies. These aims are geared to transforming the evidence-base and resources available to aging women for navigating midlife and beyond.